PROJECT SUMMARY/ABSTRACT. Strong, long lasting, T cell mediated protection against lethal heterosubtypic challenge can be generated by intranasal priming with wild type or attenuated cold adapted strains of Influenza A virus. By challenging with virus of a different subtype we are able to focus on the role of memory T cells specific for the conserved core proteins of the influenza virus in the absence of preexisting antibody to the coat proteins of the challenge virus. The T cell memory does not prevent infection of the lung epithelia following challenge but leads to enhanced numbers and earlier expansion of virus specific CD4 and CD8 T cells in the lung. We have shown that there are marked changes in lung message for inflammatory cytokines and chemokines in the early part of the response and a later reduction in the recruitment of macrophages and neutrophils with the potential to mediate immunopathology. There is also an accelerated antibody response, an earlier clearance of the virus, less weight loss and 100% survival after challenge with a viral dose 100s of times greater than the lethal dose. Enhanced survival is abolished on removal of CD8 and is diminished upon removal of CD4 T cells. We believe that memory CD4 and CD8 T cells contribute in a number of ways to prevent the more damaging effects of lethal viral challenge. This proposal aims to elucidate just how T cell memory protects against lethal challenge and promotes survival and will test the following four hypotheses: 1. The memory CD4 and CD8 T cells already resident in the lung make an early response to antigen that leads to an altered pattern of cytokine and chemokine secretion. 2. It is the responses of memory T cells that bring about the key changes seen in primed mice. 3. The early changes in the cytokine and chemokine expression seen in primed mice lead to the downstream effects that contribute to the enhanced survival. 4. Memory T cells can clear virus in the absence of neutralizing antibodies.